Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In IDDM, T-cells are postulated to mediate the destruction of pancreatic beta-cells. We analyzed peripheral blood mononuclear cell (PBMC) responses to human insulin, glutamate decarboxylase GAD65, tyrosine phosphatase ICA512, glucagon, membrane preparations of RIN cells and human pancreas, and three control antigens (La = nuclear cell antigen, tetanus toxoid, and phytohemagglutinin). A total of 28 patients with newly diagnosed IDDM, 9 antibody-positive (Ab+) first-degree relatives, and 16 healthy control subjects were included. Increased proliferative responses to pancreatic islet cell antigens were observed in diabetic patients and in Ab+ relatives compared with control subjects, whereas T-cell reactivity to nonpancreatic control antigens was similar between the study groups. The highest differences in the magnitude of proliferative responses were seen for ICA512, followed by membrane preparations of RIN cells, GAD65, and human pancreas. Few subjects reacted with insulin or glucagon. Interestingly, Ab+ relatives showed higher T-cell reactivity with respect to stimulation indexes and prevalences than newly diagnosed diabetic patients, and as many as 89% of Ab+ relatives showed proliferation to more than one islet cell antigen preparation in comparison to 43% of newly diagnosed diabetic patients and none of the control subjects. Statistical analysis revealed significant positive correlation of insulin autoantibody levels with the levels of insulin-specific T-cells in Ab+ relatives, but no relation of PBMC responses to age, sex, or HLA-DR haplotypes. Our results demonstrate the simultaneous existence of various autoreactive T-cells specific for islet cell antigens in the prediabetic period. These T-cells may play a significant role in the pathogenesis of the disease.
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PMID:Cellular immune response to diverse islet cell antigens in IDDM. 863 55

Protein tyrosine phosphatases (PTPs) play important roles in cell growth and differentiation of normal and tumor cells. In this study, we analyzed the PTP profile in two pancreatic islet tumor cell lines. Transcripts were isolated from alphaTC-1 (glucagon-secreting) and betaTC-1 (insulin-secreting) cell lines for templates. A pair of degenerative primers, based on the conserved regions of known PTPs, was used to amplify the transcripts by polymerase chain reaction. A total of 1,620 clones was examined by restriction enzyme analysis and cDNA sequencing. Twenty-one PTPs were identified, including nine cytosolic PTPs (TcPTP, P19PTP, PTP1B, PTPMEG, PTP1C, SYP, PTPH1, PTPL1, and PTPD1), nine transmembrane PTPs (PTPdelta, PTPgamma, PTPkappa, DEP-1, IA-2, LAR, PTPalpha, PTPNE3, and PTPepsilon), and three new PTPs--PTPmu-like PTPkappa-like, and IA-2beta. An RNase protection assay demonstrated that some of these PTPs were expressed predominantly in glucagonoma (i.e., PTPdelta and IA-2) and others in insulinoma (i.e., PTP1C, PTPkappa, and PTPNE3) cells. In this report, we present the first profile of PTPs in alpha and beta tumor cell lines.
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PMID:Profile and differential expression of protein tyrosine phosphatases in mouse pancreatic islet tumor cell lines. 959 14

Factors associated with residual insulin secretion and spontaneous remission in Type 1 diabetic patients are important in the evaluation of treatment aimed at modifying the natural history of Type 1 DM. We investigated the effect of parameters at onset on residual beta cell function in 215 Type 1 DM children and adolescents. Blood gas analysis, HLA, GAD and IA-2 antibodies before the start of insulin treatment were recorded for each patient. Residual C-peptide secretion was assessed by the glucagon test, and parameters of metabolic control (HbA1c and insulin dose U kg(-1) day(-1)) were examined at disease onset and after 3, 6, and 12 months. Residual C-peptide secretion throughout the first year of disease was significantly reduced in patients with disease onset before age 5. Multiple regression analysis showed that low pH at onset showed a significant and independent association with reduced C-peptide at 3 months (p = 0.02) and that the detection of GAD antibodies had a significant independent association with decreased C-peptide secretion at 6 months of follow-up (p = 0.02). Insulin requirement was higher in the youngest patients group and in patients with GAD antibodies. Spontaneous insulin remission (HbA1c <6% and insulin <0.3 U kg(-1) day(-1)) occurred in 22/192 (11%) patients at 3 months of follow-up, in 15/190 (8%) patients at 6 months and in 8/169 (5%) patient at 12 months. Remission was more prevalent in older patients (p = 0.01) and in patients without detectable GAD antibodies: (14/64 vs 8/128, p = 0.001). Sex, IA-2 antibodies and HLA DR were not independently associated with C-peptide secretion, insulin requirement or remission in the first year of Type 1 DM. This study confirms the association of young age, severe acidosis at disease onset, and GAD antibodies with decreased residual beta-cell function and spontaneous remission during the first year of insulin treatment. These factors should be considered in trials evaluating therapies to retain beta-cell function and induce remission at and after disease onset.
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PMID:Parameters associated with residual insulin secretion during the first year of disease in children and adolescents with Type 1 diabetes mellitus. 979 85

Activated immune cells contribute to the development of diabetes mellitus in multiple low-dose streptozotocin-treated mice. However, a role in the process for MHC Class I restricted T-cells remains a matter of debate. In this study, we examined by confocal microscopy the pancreatic expression of MHC Class I protein, insulin, and ICA 512 protein tyrosine phosphatase in C57BL/Ks mice given 40 mg/kg bw streptozotocin IP on 5 consecutive days. All animals were hyperglycemic from Day 7 and onwards. A loss of ICA 512 from the central portions of the islets was noted on Day 3. On Day 7, an increase in MHC Class I expression, confined primarily to immune cells in the exocrine pancreas and the periinsular areas, was detected. Later, several MHC class I/glucagon and some MHC class I/insulin double-positive cells were found. The insulitis was maximal on Day 14 and declined thereafter. The induction of MHC Class I expression in endocrine cells, occuring only after the cellular infiltration and when the animals were diabetic, indicates that the immune component of the disease does not depend on MHC Class I-restricted cytotoxic T-cells but rather comprises a non-antigen-specific process. (J Histochem Cytochem 48:761-767, 2000)
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PMID:Expression of pancreatic islet MHC class I, insulin, and ICA 512 tyrosine phosphatase in low-dose streptozotocin-induced diabetes in mice. 1082 Jan 50

IA-2, a member of the protein tyrosine phosphatase family, represents a major target autoantigen in type 1 diabetes. To study the regulation of IA-2 gene expression, we used INS-1 insulinoma cells to analyze beta-cell signal transduction pathways as well as the effect of metabolic and hormonal factors involved in the regulation of the insulin secretory pathway. Quantitative competitive reverse transcriptase-polymerase chain reaction revealed that an increase of cellular cAMP mediated by forskolin (10 micromol/l, 24 h) or 3-isobutyl-1-methylxanthine (100 micromol/l, 24 h) induced maximal stimulation of IA-2 mRNA levels (451 +/- 85 and 338 +/- 86% compared with basal conditions; P < 0.001). In contrast, activation of protein kinase C (PKC) by short-term treatment with phorbol 12-myristate 13-acetate (PMA) (1 micromol/l, 6 h) did not alter IA-2 expression, whereas depletion of PKC by prolonged culturing (24 h) exerted a significant inhibition (57 +/- 24%; P < 0.05). cAMP-dependent upregulation was confirmed by the findings that glucagon (10 micromol/l, 24-48 h) increased levels of IA-2 mRNA (190 +/- 35%; P < 0.05), whereas short-term incubation with high glucose concentration showed no effect. However, prolonged incubation in high glucose (21 mmol/l) induced a time- and dose-dependent increase of IA-2 mRNA expression, reaching maximal values after 144 h (285 +/- 68%; P < 0.05). These studies demonstrate that stimuli of insulin secretion that operate by activation of adenylate cyclase generating cAMP significantly increase IA-2 gene expression. In contrast, activation of PKC by high glucose concentration or PMA exerted no effect, suggesting that IA-2 gene expression is not simply coupled to insulin secretion, but may be involved in the fine regulation of beta-cell function. These findings may be important to clarify the function of IA-2 in beta-cells and elucidate mechanisms involved in the induction of autoimmunity to IA-2.
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PMID:Regulation of the diabetes-associated autoantigen IA-2 in INS-1 pancreatic beta-cells. 1090 70

This study determined the prevalence and significance of autoantibodies to GAD65 (GAD Ab), insulin (IAA), tyrosine-like phosphatase (IA2) and islet-cell (ICA) in a group of 213 young Malaysian Type 1 diabetics, diagnosed before the age of 40 years. Venous blood was taken at fasting, and at 6 minutes post-glucagon (1 mg i.v.). IAA was detected in 47.4%, GAD Ab in 33.8%, IA2 in 8.9% and ICA in 1.4% of the subjects. When based on post-glucagon C-peptide level of 600 pmol/L, 172 (80.7%) patients had inadequate pancreatic reserve, while the remainder 41(19.3%) showed normal response. The autoantibodies, either alone or in combination, were detectable in both groups of patients; higher prevalence in those with poor or no beta-cell function (73.3% versus 46.3%, p = 0.0001). Although the prevalence of GAD Ab was highest in newly diagnosed patients (< 5 years), unlike IA2 and ICA, the marker remained detectable in 24-25% of those patients with long-standing disease. Nineteen patients could probably belong to the "latent autoimmune diabetes in adults (LADA)" subset, where pancreatic reserve was adequate but patients had detectable autoantibodies and insulin-requiring. On the other hand, 68 of the 213 patients (32%) were seronegative, but presented with near or total beta-cell destruction. Thus, as has also been suggested by others, there is indeed etiological differences between the Asian and the Caucasian Type 1 diabetics, and, there is also the possibility that other, but unknown autoantigens are involved in causing the pancreatic damage.
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PMID:Autoimmune markers in young Malaysian patients with type 1 diabetes mellitus. 1120 Jul 11

A tyrosine phosphatase-like protein, IA-2, is a major autoantigen in Type 1 diabetes but its role in islet function is unclear. Tyrosine phosphorylation mediates regulation of cellular processes such as exocytosis, cell growth, and cell differentiation. To investigate the potential involvement of IA-2 in islet differentiation and insulin secretion, we analyzed by immunohistochemistry expression of IA-2 during islet development in fetal rats and during the maturation of insulin secretory responses after birth. In the fetus, IA-2 immunoreactivity was detected in primitive islets positive for insulin and glucagon at 12 days' gestation. Subsequently, IA-2 was only weakly detectable in the fetal pancreas. In neonatal rat, a progressive increase in IA-2 immunoreactivity was observed in islets from very low levels at 1 day of age to moderate labeling at 10 days. In the adult, relatively high levels of IA-2 were detected in islets, with heterogeneous expression in individual cells within each islet. IA-2 marks a population of endocrine cells that transiently appear early in pancreatic ontogeny. Islet IA-2 expression reappears after birth concomitant with the development of mature insulin secretory responses, consistent with a role for this protein in regulated hormone secretion.
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PMID:Expression of the protein tyrosine phosphatase-like protein IA-2 during pancreatic islet development. 1137 23

We characterised a consecutive cohort of 132 youth onset diabetic individuals (age at onset<30 years, mean duration of disease 5.5+/-6.0 years) from North India, by serological determination of the determination of the islet cell autoantibodies, GAD(65) and IA2, and clinically for coexisting autoimmune thyroid disease, malnutrition and pancreatic calcification. Five types of diabetes were delineated: Type 1 (37%), ketosis resistant (32%), Type 2 (13%), fibrocalculous pancreatopathy (11%) and autoimmune polyglandular syndrome (7%). C-peptide response to glucagon was assessed in a representative subset of 50 patients with Type 1, ketosis resistant, and autoimmune polyglandular syndrome. A total of 22.4% of Type 1 and 30% of autoimmune polyglandular syndrome subjects showed both GAD(65) plus IA-2 autoantibody positivity, significantly more than the 4.7% positivity shown by the ketosis resistant type. However, GAD(65) antibody positivity alone was seen in 38% of ketosis resistant subjects which was significantly more than the 14.2 and 10% positivity seen in Type 1 and autoimmune polyglandular groups, respectively. The fibrocalculous pancreatopathy group showed GAD(65) plus IA-2 autoantibody positivity in 14.2% and GAD(65) autoantibody alone positivity in 7.1%. 26 and 60%, respectively, of the Type 1 and autoimmune polyglandular syndrome groups had thyroid microsomal autoantibody positivity. Type 1 showed significantly less C-peptide response to glucagon when compared to the ketosis resistant and autoimmune polyglandular syndrome groups. The controls and Type 2 diabetic individuals tested negative for islet cell autoimmunity markers. These findings demonstrate a role of islet cell autoimmunity in the pathogenesis of four out of the five clinical types of youth onset diabetes seen in North India.
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PMID:Islet cell autoimmunity in youth onset diabetes mellitus in Northern India. 1137 13

The incidence of type 2 diabetes mellitus (DM) in children and adolescents has substantially increased over the past decade. The present study was conducted to evaluate the beta-cell response to intravenous glucagon (a non-glucose secretagogue) in children with type 2 DM. Twenty pediatric patients with type 2 DM were compared to 15 control subjects matched for body mass index and sexual maturation. The patients' ages ranged between 10 and 19 years. The duration of DM ranged from 1 to 5 years. Nine patients were on insulin treatment and 11 were on diet alone (3 patients) or metformin (8 patients). The criteria for type 2 DM were absent islet cell (IA-2) and glutamic acid decarboxylase (GAD65) antibodies and a fasting serum C-peptide level of > or = 0.23 nmol/l. Plasma glucose and serum C-peptide levels were determined in the fasting state and six minutes after an intravenous injection of 1 mg of glucagon. The fasting and stimulated plasma glucose levels and the fasting serum C-peptide levels (1.02 +/- 0.43 vs 0.79 +/- 0.26 nmol/l, p < 0.05) were higher in the patients with DM compared to weight-matched control subjects. While the absolute C-peptide responses to glucagon were not different between the two groups, the stimulated C-peptide to glucose ratios were significantly lower in the patients with DM compared to controls (0.039 +/- 0.026 vs 0.062 +/- 0.033, p < 0.05). Patients with DM treated with diet or oral therapy had significantly greater basal and stimulated C-peptide concentrations, incremental C-peptide, and C-peptide to glucose ratios than patients on insulin treatment. Both the fasting and the stimulated C-peptide levels were inversely correlated with the duration of DM (r = -0.53, p < 0.05). HbA1c at one year follow-up was inversely correlated with glucagon-stimulated C-peptide levels at the time of the study (r = -0.658, p < 0.01) and positively correlated with the duration of diabetes (r = 0.671, p = 0.002). The apparently normal serum C-peptide levels measured after glucagon challenge in these children with type 2 DM reflect their higher glucose levels. The lower stimulated C-peptide to glucose ratios in these children with type 2 DM compared to normal controls demonstrate their diminished beta-cell response to intravenous glucagon, a non-glucose secretagogue. Among the patients with DM, a higher glucagon-stimulated serum C-peptide response was associated with diet/metformin treatment, a shorter duration of DM and predicted improved glycemic control up to one year later. Thus, the fasting and glucagon-stimulated serum C-peptide levels provide an estimate of the potential insulin secretory capacity of the beta-cell and may predict glycemic control in pediatric type 2 DM.
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PMID:Beta-cell response to intravenous glucagon in African-American and Hispanic children with type 2 diabetes mellitus. 1182 82

To study whether antibodies to glutamic acid decarboxylase (GADab) are associated with subclinical beta-cell damage and impaired insulin secretion, we screened 441 nondiabetic patients with autoimmune thyroiditis (AT) for GADab, and 15 (3.4%) were found positive. Antibodies to IA-2 were found in two GADab+ and one GADab- patients. We matched 11 GADab+ and 13 GADab- AT patients who were euthyroid on thyroxin supplementation, and 13 control subjects for sex, age, and body mass index and measured insulin, C-peptide, and glucagon response to glucose and arginine at three blood glucose concentrations (fasting, 14 mmol/liter, >25 mmol/liter). In the fasting state, all groups had similar blood glucose concentration and HbA1c level, but the serum insulin concentration was higher in the AT patients compared with the control subjects (P < 0.04). The acute insulin response to arginine was lower in GADab+ than in GADab- thyroiditis subjects at glucose concentration of 14 and >25 mmol/liter (AIR(14): 76.8 +/- 52.0 vs. 158.2 +/- 118.2 mU/liter, P = 0.040; AIR(>25): 84.3 +/- 64.4 vs. 167.9 +/- 101.5 mU/liter, P = 0.035). In conclusion, GADab were associated with a decreased insulin secretion capacity in nondiabetic subjects with thyroiditis, which suggests that GADab positivity could be a marker of subclinical insulitis.
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PMID:Glutamic acid decarboxylase antibody positivity is associated with an impaired insulin response to glucose and arginine in nondiabetic patients with autoimmune thyroiditis. 1188 83


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